The goal of this proposal is to test the hypothesis that elevated fibrinogen, either alone or with a predisposition to atherosclerosis, causes or contributes to cardiovascular diseases. To do this, three mouse models with elevated fibrinogen levels will be developed and examined. The first model, a transgenic model that contains randomly inserted copies of the murine fibrinogen genes, will be created by pronuclear injection of fertilized mouse embryos. A second model with a specific targeted duplication of the murine fibrinogen gene locus in embryonic stem cells and resultant altered animals will be generated according to a recently developed targeted duplication procedure. A third model of hyperfibrinogenemia with a combined deficiency in apolipoprotein E will be constructed by cross breeding hyperfibrinogenemic mice with apolipoprotein E null mice. The incidence of atherosclerosis and progression of the disease will be assessed morphometrically in these genetically altered mice by measurements of atherosclerotic lesion size and percent surface area of the aorta affected.